Drug Res (Stuttg) 2013; 63(10): 532-539
DOI: 10.1055/s-0033-1347237
Original Article
© Georg Thieme Verlag KG Stuttgart · New York

The Effects of Tianeptine, Olanzapine and Fluoxetine on the Cognitive Behaviors of Unpredictable Chronic Mild Stress-exposed Mice

E. Gumuslu
1   Department of Medical Genetics, Kocaeli University Medical Faculty, Kocaeli, Turkey
O. Mutlu
2   Department of Pharmacology, Kocaeli University Medical Faculty, Kocaeli, Turkey
D. Sunnetci
1   Department of Medical Genetics, Kocaeli University Medical Faculty, Kocaeli, Turkey
G. Ulak
2   Department of Pharmacology, Kocaeli University Medical Faculty, Kocaeli, Turkey
I. K. Celikyurt
2   Department of Pharmacology, Kocaeli University Medical Faculty, Kocaeli, Turkey
N. Cine
1   Department of Medical Genetics, Kocaeli University Medical Faculty, Kocaeli, Turkey
F. Akar
2   Department of Pharmacology, Kocaeli University Medical Faculty, Kocaeli, Turkey
› Author Affiliations
Further Information

Publication History

received 27 February 2013

accepted 09 May 2013

Publication Date:
18 June 2013 (online)



Strong evidence indicates that impaired cognition is a core element of depression, and antidepressant treatment may ameliorate cognitive impairments experienced by depressive patients. Present study was performed to investigate effects of chronic tianeptine (5 mg/kg) or olanzapine (2.5 mg/kg) administration on cognitive behaviors of unpredictable chronic mild stress (UCMS)-exposed mice and to compare these effects to those induced by widely used SSRI antidepressant fluoxetine (15 mg/kg) in mice.


To investigate effects of these drugs, the Morris water maze test (MWM), elevated plus maze test (EPM) and radial arm maze test (RAM) were used. The effects of stress and drugs on gene expression in the hippocampus was determined by quantitative Real Time-PCR.


In MWM test, fluoxetine significantly increased escape latency of non-stressed mice in acquisition sessions and decreased time spent in escape platform quadrant in probe trial; tianeptine and olanzapine decreased enhancement in escape latency, and only olanzapine significantly enhanced attenuation in time spent in the escape platform quadrant in UCMS-exposed mice. In EPM test, all drugs significantly decreased enhancement in transfer latency in UCMS-exposed mice. In RAM test, fluoxetine significantly increased number of errors made by both non-stressed and UCMS-exposed mice.


Quantitative real-time PCR revealed that CREB and BDNF gene expression levels were significantly decreased in UCMS-exposed group, and this effect was significantly reversed by each of drugs tested. Our results seem to be test dependent and should be further investigated using different learning and memory tasks.

  • References

  • 1 Conrad CD, Galea LAM, Kuroda Y et al. Chronic stress impairs rat spatial memory on the Y maze, and this effect is blocked by tianeptine pretreatment. Behav Neurosci 1996; 110: 1321-1334
  • 2 Alfonso J, Frasch AC, Flugge G. Chronic stress, depression and antidepressants: Effects on gene transcription in the hippocampus. Rev Neurosci 2005; 16: 43-56
  • 3 Mu JS, Li WP, Yao ZB et al. Deprivation of endogenous brain-derived neurotrophic factor results in impairment of spatial learning and memory in adult rats. Brain Res 1999; 835: 259-265
  • 4 Aydemir C, Yalcin ES, Aksaray S et al. Brain-derived neurotrophic factor (BDNF) changes in the serum of depressed women. Prog Neuropsychopharmacol Biol Psychiatry 2006; 30: 1256-1260
  • 5 Willner P, Muscat R, Papp M. Chronic mild stress-induced anhedonia: a realistic animal model of depression. Neurosci Biobehav Rev 1992; 16: 525-534
  • 6 Ducottet C, Belzung C. Behaviour in the elevated plus-maze predicts coping after subchronic mild stress in mice. Physiol Behav 2004; 81: 417-426
  • 7 Hlinak Z, Krejci I. MK-801 induced amnesia for the elevated plus-maze in mice. Behav Brain Res 2002; 131: 221-225
  • 8 Beuzen A, Belzung C, Roullet P. Drug effects in a radial maze designed for dissociation of cues used by mice. Pharmacol Biochem Behav 1994; 48: 23-29
  • 9 Savli H, Karadenizli A, Kolayli F et al. Expression stability of six housekeeping genes: A proposal for resistance gene quantification studies of Pseudomonas aeruginosa by real-time quantitative RT-PCR. J Med Microbiol 2003; 52: 403-408
  • 10 Mutlu O, Ulak G, Celikyurt IK et al. Effects of olanzapine, sertindole and clozapine on learning and memory in the Morris water maze test in naive and MK-801-treated mice. Pharmacol Biochem Behav 2011; 98: 398-404
  • 11 Ulak G, Mutlu O, Yıldız Akar F et al. Neuronal NOS inhibitor 1-(2-trifluoromethylphenyl)-imidazole augment the effects of antidepressants acting via serotonergic system in the forced swimming test in rats. Pharmacol Biochem Behav 2008; 90: 563-568
  • 12 Katz RJ, Sibel M. Animal model of depression: tests of three structurally and pharmacologically novel antidepressant compounds. Pharmacol Biochem Behav 1982; 16: 973-977
  • 13 Uekermann J, Daum I, Peters S et al. Depressed mood and executive dysfunction in early Parkinson’s disease. Acta Neurol Scand 2003; 107: 341-348
  • 14 Von Gunten A, Fox NC, Cipolotti L et al. A volumetric study of hippocampus and amygdala in depressed patients with subjective memory problems. J Neuropsychiatry Clin Neurosci 2000; 12: 493-498
  • 15 Song L, Che W, Min-wei W et al. Impairment of the spatial learning and memory induced by learned helplessness and chronic mild stress. Pharmacol Biochem Behav 2006; 83: 186-193
  • 16 Branchi I, Francia N, Alleva E. Epigenetic control of neurobehavioural plasticity: The role of neurotrophins. Behav Pharmacol 2004; 15: 353-362
  • 17 Schulman H. Protein phosphorylation in neuronal plasticity and gene expression. Curr Opin Neurobiol 1995; 5: 375-381
  • 18 Xu H, Luo C, Richardson JS et al. Recovery of hippocampal cell proliferation and BDNF levels, both of which are reduced by repeated restraint stress, is accelerated by chronic venlafaxine. Pharmacogenomics 2004; 4: 322-331
  • 19 Alfonso J, Frick LR, Silberman DM et al. Regulation of hippocampal gene expression is conserved in two species subjected to different stressors and antidepressant treatments. Biol Psychiatry 2006; 59: 244-251
  • 20 Ernfors P, Ibáñez CF, Ebendal T et al. Molecular cloning and neurotrophic activities of a protein with structural similarities to nerve growth factor: developmental and topographical expression in the brain. Proc Natl Acad Sci USA 1990; 87: 5454-5458
  • 21 Scaccianoce S, Del Bianco P, Caricasole A et al. Relationship between learning, stress and hippocampal brain-derived neurotrophic factor. Neuroscience 2003; 121: 825-828
  • 22 Lu B. BDNF and activity-dependent synaptic modulation. Learn Mem 2003; 10: 86-98
  • 23 Barad M, Bourtchouladze R, Winder DG et al. Rolipram, a type IV-specific phosphodiesterase inhibitor, facilitates the establishment of long-lasting long-term potentiation and improves memory. PNAS USA 1998; 95: 15020-15025
  • 24 Thome J, Sakai N, Shin K et al. cAMP response element-mediated gene transcription is upregulated by chronic antidepressant treatment. J Neurosci 2000; 20: 4030-4036
  • 25 Mennini T, Mocaër E, Garattini S. Tianeptine, a selective enhancer of serotonin uptake in rat brain. Naunyn-Schmiedebergs Arch Pharmacol 1987; 336: 478-482
  • 26 Wilde MI, Benfield P. Tianeptine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in depression and coexisting anxiety and depression. Drugs 1995; 49: 411-439
  • 27 Czeh B, Michaelis T, Watanabe T et al. Stress-induced changes in cerebral metabolites, hippocampal volume, and cell proliferation are prevented by antidepressant treatment with tianeptine. Proc Natl Acad Sci USA 2001; 98: 12796-12801
  • 28 Vouimba RM, Munoz C, Diamond DM. Influence of the antidepressant tianeptine and stress on the expression of synaptic plasticity in the hippocampus and amygdala. Soc Neurosci 2003; 376: 6
  • 29 File SE, Mabbut PS. Effects of tianeptine in animal models of anxiety and on learning and memory. Drug Develop Res 1991; 23: 47-56
  • 30 Jaffard R, Mocear E, Poignant JC et al. Effects of tianeptine on spontaneous alternation and on simple and concurrent spatial discrimination learning in mice. Behav Pharmacol 1991; 2: 20-25
  • 31 Marston HM, Martin FD, Papp M et al. Attenuation of chronic mild stress-induced ‘anhedonia’ by asenapine is not associated with a ‘hedonic’ profile in intracranial self-stimulation. J Psychopharmacol 2011; 25: 1388-1398
  • 32 Bai O, Chlan-Fourney J, Bowen R et al. Expression of brain-derived neurotrophic factor mRNA in rat hippocampus after treatment with antipsychotic drugs. J Neurosci Res 2003; 71: 127-131